Trimethylamine-N-oxide (TMAO), a microbiota-dependent metabolite derived from trimethylamine (TMA)-containing nutrients that are abundant in a Western diet, enhances both platelet responsiveness and in vivo thrombosis potential in animal models and predicts incident atherothrombotic event risks in clinical studies. Here, utilizing a mechanism-based inhibitor approach targeting a major microbial TMA-generating enzyme (CutC/D), we developed potent, time-dependent and irreversible inhibitors that do not affect commensal viability. In animal models, a single oral dose of a CutC/D inhibitor significantly reduced plasma TMAO levels for up to 3 days and rescued diet-induced enhanced platelet responsiveness and thrombus formation, without observable toxicity or increased bleeding risk. The inhibitor selectively accumulated within intestinal microbes to millimolar levels, a concentration over a million-fold higher than needed for a therapeutic effect. These studies reveal that mechanism-based inhibition of gut microbial TMA/TMAO production reduces thrombosis potential, a critical adverse complication in heart disease. They also offer a generalizable approach for the selective non-lethal targeting of gut microbial enzymes linked to host disease, while limiting systemic exposure of the inhibitor in the host.

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Barrington et al. examined the effect of four human diets (American, Mediterranean, Japanese, and Maasai/ketogenic) on metabolic health across four mouse...

Although they are increasing, the rates of ICD therapy after CA remain very low. There are gross discrepancies by race. At a time when newer indications for ICD implantation are emerging, efforts should be focused on identifying the causes of this underutilization and discrepancies in survivors of CA.

The adenosine agonist 2-(4-(2-carboxyethyl)phenylethylamino)-5′-N-ethylcarboxamidoadenosine (CGS21680) was recently reported to be selective for the A 2A adenosine receptor subtype, which mediates its hypotensive action. To investigate structurelactivity relationships at a distal site, CGS21680 was derivatized using a functionalized congener approach. The carboxylic group of CGS21680 has been esterified to form a methyl ester, which was then treated with ethylenediamine to produce an amine congener. The amine congener was an intermediate for acylation reactions, in which the reactive acyl species contained a reported group, or the precursor for such. For radioiodination, derivatives of p-hydroxyphenylpropionic, 2-thiophenylacetic, and paminophenylacetic acids were prepared. The latter derivative (PAPA-APEC) was iodinated electrophilically using [ 125 I]iodide resulting in a radioligand which was used for studies of

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The gut microbiota has been associated with many different disorders, including cardiovascular diseases. A new study by Jie and colleagues is the first large case–control study to examine directly the enrichment of certain communities of gut bacteria in patients with atherosclerotic cardiovascular disease compared with control individuals.